Stem Cell Environment and Skeletal Muscle Homeostasis

Stem cells are important in the maintenance and repair of many tissues all along the life span. It is the case
in skeletal muscle, which presents high plasticity and regenerative properties. Normal skeletal muscle
mobilizes tissue-associated endogenous stem cells, mainly satellite cells, and also upstream peri-
endothelial stem cells, to repair damaged myofibres.

A key issue we address is the tissue environment in which muscle stem cells are activated. Environment
plays important roles in the behavior of muscle stem cells and myogenic cells, although the mechanisms
are poorly unknown. Various cell types in the vicinity of stem cells communicate with each other to correctly
drive regeneration. We explore the roles of immune cells (inflammation), endothelial and peri-endothelial
cells (angiogenesis) and interstitial cells (fibrosis) in both myogenic cell fate in normal healthy regenerating
muscle and in the pathogenesis of muscular dystrophies. Indeed, degenerative myopathies are
characterized by alteration in the environment of muscle stem cells, such as the presence of chronic
inflammation and fibrosis, which are detrimental for both tissue repair and cell therapies.

Macrophages

Skeletal muscle regeneration is associated with the presence of macrophages. Two main inflammatory
types of macrophages are present during skeletal muscle regeneration, which exert distinct effects on
myogenic cells. Soon after injury, inflammatory monocytes enter into the damaged muscle and these
inflammatory macrophages stimulate the proliferation of myogenic precursor cells. Later, they switch their
phenotype into anti-inflammatory macrophages that sustain myogenic differentiation and myofibre growth.
Macrophages can be considered as a stromal support for myogenic cells that helps the sequential steps of
skeletal muscle regeneration and which use may be of interest to improve myogenic cell therapies.

Molecular mechanisms that control macrophage inflammatory states during skeletal muscle regeneration
start to be understood, among which AMPK, the main energetic sensor in the cells, which controls the
skewing towards the anti-inflammatory state. We also aim at identifying the cues secreted by macrophages
that support myogenesis. We also investigate the roles and identity of macrophage populations during
degenerative myopathies, during which the whole skeletal muscle homeostasis is unbalanced, and
particularly the impact of macrophages on myogenesis and fibrosis in this pathological context.

Vessel cells

Whatever their status, satellite cells and myogenic precursor cells are close to capillaries. Endothelial and
peri-endothelial cells develop specific interactions with myogenic cells. Endothelial cells and myogenic
precursor cells interact to stimulate each other growth and differentiation. On the contrary peri-endothelial
cells (smooth muscle cells) promote the self-renewal and maintain into quiescence of myogenic cells. A
main regulator of these effects is the Angipoietin-1-Tie-2-ERK signaling pathway.

We aim at understanding the molecular regulation of the coupling between angiogenesis and myogenesis
during skeletal muscle regeneration, as well as identifying whether these interactions are altered during
degenerative and inflammatory myopathies.

Muscle stem cell homeostasis

Although extrinsic factors, coming from their environment, participate in the regulation of muscle stem cell
fate, intrinsic molecular pathways also control this process. We are investigating the role of such
factors, notably in the self-renewal of muscle stem cells. We aim at understanding whether those intrinsic
factors may be altered by systemic changes such as metabolic alteration.

Our goal is to identify new functions for the cell neighbors of muscle stem cells beside their canonical
properties (regulation of inflammation for macrophages, supply of oxygen and nutriments for vessel cells)
and how muscle stem cells are controlled by their closest environment in both normal and pathological
contexts. The identification of new molecules or novel functions of already known pathways are the basis
for expanding our current understanding about skeletal muscle plasticity and its pathophysiology.